Sickle cell disease (SCD) is a serious genetic disease that affects tens of thousands of people in the United States and many more throughout the world. It causes pain, disability, organ damage, and death. Life expectancy for its victims is only mid-40's. Few effective treatments are available. Now, based on the results of recent studies, nitric oxide (NO) donors show promise for effective treatment of SCD patients. The hallmark of SCD is the aggregation (polymerization) of sickle cell hemoglobin (Hb S) in the deoxygenated state. Increasing aggregation of Hb S within a red blood cell (RBC) leads to gelling of the protein and eventually sickling of the cell. In SCD patients, the treatment rationale is to reduce RBC sickling by increasing the relative concentration of non-aggregating forms of hemoglobin (Hb). We believe that a new class of NO donors can produce that effect. Based on this premise, we propose to demonstrate the feasibility of developing this new class of NO donors. The Phase I work will be focused on producing the candidate compounds, determining their kinetics of reactivity with the biological targets, and assessing their effectiveness at preventing RBC sickling in vitro. PROPOSED COMMERCIAL APPLICATIONS: During Phase I we expect to show the advantageous--and possibly unique-- chemical and pharmacological properties of a new class of NO donors for the treatment of SCD. A follow-on Phase II program will focus on optimization of SCD therapy via the novel reactivity that is promoted by these new NO donors. The resulting new therapeutic capabilities would benefit hundreds of thousands of SCD victims worldwide.